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Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

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Abstract

Rationale

Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models.

Objectives

The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects.

Methods

Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure.

Results

Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90 % cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016).

Conclusion

The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

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Acknowledgments

We acknowledge Crystal Reyns for the technical assistance, Kevin Costa for coding the original behavioral program version, and David E. Nichols for the generous (±)-MDMA HCl donation.

Authorship contributions

Participated in research design: Banks

Conducted experiments: Smith

Contributed new reagents: Blough

Recorded data analysis: Banks

Wrote or contributed to the writing of the manuscript: Smith, Blough, and Banks

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA, 23298, USA

    Douglas A. Smith & Matthew L. Banks

  2. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA

    Bruce E. Blough

Authors
  1. Douglas A. Smith
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  2. Bruce E. Blough
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  3. Matthew L. Banks
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Corresponding author

Correspondence to Matthew L. Banks.

Ethics declarations

The experiments were conducted in accordance with the eighth edition of Guide for the Care and Use of Laboratory Animals (2011) and under Institutional Animal Care and Use Committee-approved research and enrichment protocols.

Funding

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under award number R01DA031718 and R01DA012970 and institutional professional development funds. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Mr. Smith declares no conflicts of interest. Dr. Blough declares NIH has funded his research. Dr. Banks declares NIH has funded his research. During the past 3 years, he has received compensation as a collaborator with Purdue pharmaceutical for projects related to opioid pharmacology and drug development. Dr. Banks declares that the present study was not related to this professional relationship and should not be perceived as constituting a conflict of interest.

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Smith, D.A., Blough, B.E. & Banks, M.L. Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys. Psychopharmacology 234, 117–127 (2017). https://doi.org/10.1007/s00213-016-4444-1

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  • DOI: https://doi.org/10.1007/s00213-016-4444-1

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